Method for promoting upper gastrointestinal bicarbonate secretion

ABSTRACT

Provided is a method for promoting upper gastrointestinal bicarbonate secretion in a mammalian subject, which comprises administering an effective amount of a compound of Formula (I): 
                         
to a subject in need thereof, wherein W 1 , W 2 , R 1 , R 2 , x 1 , x 2 , Y and A are herein defined. The compound is also useful for protecting the upper gastrointestinal tract of a mammal from mucosal damage.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a continuation of application Ser. No. 11/850,271 filed Sep. 5,2007, which claims the benefit of Provisional Application No. 60/842,382filed Sep. 6, 2006, the whole contents of which are hereby incorporatedby reference.

TECHNICAL FIELD

The present invention relates to a method for promoting gastrointestinalbicarbonate secretion in a mammalian subject.

The present invention further relates to a method for protecting thegastrointestinal tract in a mammalian subject from mucosal damage.

BACKGROUND ART

Secretion of bicarbonate provides a mucosal protection at the epithelialsurfaces in the gastrointestinal tracts. The mucosa is exposed tonoxious agents, including high concentrations of ethanol and medicationssuch as aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs).In each organ, bicarbonate secretion protects potential mucosal damageinduced by acid, pepsin, certain drugs such as NSAIDs, and bacterialinfection (News Physiol. Sci. 16, 23-28, 2001, the reference is hereinincorporated by reference).

Prostaglandins (hereinafter, referred to as PG(s)) are members of classof organic carboxylic acids, which are contained in tissues or organs ofhuman or other mammals, and exhibit a wide range of physiologicalactivity. PGs found in nature (primary PGs) generally have a prostanoicacid skeleton as shown in the formula (A):

On the other hand, some of synthetic analogues of primary PGs havemodified skeletons. The primary PGs are classified into PGAs, PGBs,PGCs, PGDs, PGEs, PGFs, PGGs, PGHs, PGIs and PGJs according to thestructure of the five-membered ring moiety, and further classified intothe following three types by the number and position of the unsaturatedbond at the carbon chain moiety:

Subscript 1: 13,14-unsaturated-15-OH

Subscript 2: 5,6- and 13,14-diunsaturated-15-OH

Subscript 3: 5,6-, 13,14-, and 17,18-triunsaturated-15-OH.

Further, the PGFs are classified, according to the configuration of thehydroxyl group at the 9-position, into α type (the hydroxyl group is ofan α-configuration) and β type (the hydroxyl group is of aβ-configuration).

PGE₁ and PGE₂ and PGE₃ are known to have vasodilation, hypotension,gastric secretion decreasing, intestinal tract movement enhancement,uterine contraction, diuretic, bronchodilation and anti ulceractivities. PGF₁α, PGF₂α and PGF₃α have been known to have hypertension,vasoconstriction, intestinal tract movement enhancement, uterinecontraction, lutein body atrophy and bronchoconstriction activities.

Some 15-keto (i.e., having oxo at the 15-position instead ofhydroxy)-PGs and 13,14-dihydro (i.e., having single bond between the 13and 14-position)-15-keto-PGs are known as the substances naturallyproduced by the action of enzymes during the metabolism of primary PGs.

U.S. Pat. No. 7,064,148 to Ueno et al. (the reference is hereinincorporated by reference) describes that specific prostaglandincompounds including bicyclic tautomer of 15-keto-prostaglandin compoundsopen and activate chloride channels, especially ClC channels, moreespecially ClC-2 channel.

Recent findings suggest that PGs stimulate bicarbonate secretion instomach and duodenum by acting on the PG receptors (J Physiol.Pharmacol. 50(2), 155-167, 1999, the reference is herein incorporated byreference).

On the other hand, it is reported that unoprostone isopropyl, one of the15-keto-prostaglandin compounds does not have affinity for PG receptorssuch as EP and FP receptors (Journal of Ocular Pharmacology andTherapeutics 17(5), 433-441, 2001, the reference is herein incorporatedby reference).

SUMMARY OF THE INVENTION

The present inventor conducted an intensive study and found that acertain prostaglandin compound promotes the gastrointestinal bicarbonatesecretion, thereby it is useful for protecting the gastrointestinaltract from mucosal damage, which have resulted in the completion of thepresent invention.

Namely, the present invention relates to a method for promotingbicarbonate secretion in the gastrointestinal tract in a mammaliansubject, which comprises administering to the subject in need thereof aneffective amount of a compound represented by Formula (I) and/or itstautomer:

wherein W₁ and W₂ are

R₃ and R₄ are hydrogen; or one of them is OH and the other is hydrogen;

X₁ and X₂ are hydrogen, lower alkyl or halogen, provided that at leastone of them is halogen;

R₂ is a hydrogen or lower alkyl;

Y is a saturated or unsaturated C₂₋₁₀ hydrocarbon chain, which isunsubstituted or substituted by oxo, halogen, alkyl, hydroxyl or aryl;

A is —CH₂OH, —COCH₂OH, —COOH or its functional derivative;

R₁ is a saturated or unsaturated, straight chain-, branched chain- orring-forming lower hydrocarbon, which is unsubstituted or substituted byhalogen, oxo, hydroxy, lower alkyl, lower alkoxy, lower alkanoyloxy,lower cycloalkyl, lower cycloalkyloxy, aryl, or aryloxy; lowercycloalkyl; lower cycloalkyloxy; aryl or aryloxy;

the bond between C-13 and C-14 position is double or single bond, and

the steric configuration at C-15 position is R, S, or a mixture thereof.

The present invention further relates to a method for protecting thegastrointestinal tract from mucosal damage in a mammalian subject, whichcomprises administering an effective amount of a compound represented byFormula (I) and/or its tautomer to the subject in need thereof.

DETAILED DESCRIPTION OF THE INVENTION

The compound used in the present application is represented by Formula(I):

wherein W₁ and W₂ are

R₃ and R₄ are hydrogen; or one of them is OH and the other is hydrogen;

X₁ and X₂ are hydrogen, lower alkyl or halogen, provided that at leastone of them is halogen;

R₂ is a hydrogen or lower alkyl;

Y is a saturated or unsaturated C₂₋₁₀ hydrocarbon chain, which isunsubstituted or substituted by oxo, halogen, alkyl, hydroxyl or aryl;

A is —CH₂OH, —COCH₂OH, —COOH or its functional derivative;

R₁ is a saturated or unsaturated, straight chain-, branched chain- orring-forming lower hydrocarbon, which is unsubstituted or substituted byhalogen, oxo, hydroxy, lower alkyl, lower alkoxy, lower alkanoyloxy,lower cycloalkyl, lower cycloalkyloxy, aryl, or aryloxy; lowercycloalkyl; lower cycloalkyloxy; aryl or aryloxy;

the bond between C-13 and C-14 position is double or single bond, and

the steric configuration at C-15 position is R, S, or a mixture thereof.

In the above formula, the term “halogen” is used to include fluorine,chlorine, bromine, and iodine atoms. Particularly preferable halogenatoms for X₁ and X₂ are fluorine atoms.

The term “unsaturated” in the definitions for R₁ and Y is intended toinclude at least one or more double bonds and/or triple bonds that areisolatedly, separately or serially present between carbon atoms of themain and/or side chains. According to the usual nomenclature, anunsaturated bond between two serial positions is represented by denotingthe lower number of the two positions, and an unsaturated bond betweentwo distal positions is represented by denoting both of the positions.

The term “lower” throughout the specification and claims is intended toinclude a group having 1 to 6 carbon atoms unless otherwise specified.

The term “ring” refers to lower cycloalkyl, lower cycloalkyloxy, aryl oraryloxy.

The term “lower alkyl” refers to a straight or branched chain saturatedhydrocarbon group containing 1 to 6 carbon atoms and includes, forexample, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl,pentyl and hexyl.

The term “lower alkoxy” refers to a group of lower alkyl-O—, whereinlower alkyl is as defined above.

The term “lower alkanoyloxy” refers to a group represented by theformula RCO—O—, wherein RCO— is an acyl group formed by oxidation of alower alkyl group as defined above, such as acetyl.

The term “lower cycloalkyl” refers to a cyclic group formed bycyclization of a lower alkyl group as defined above but contains threeor more carbon atoms, and includes, for example, cyclopropyl,cyclobutyl, cyclopentyl and cyclohexyl.

The term “lower cycloalkyloxy” refers to the group of lowercycloalkyl-O—, wherein lower cycloalkyl is as defined above.

The term “aryl” refers to unsubstituted or substituted aromaticcarbocyclic or heterocyclic groups, preferably mono-cyclic groups, forexample, phenyl, naphthyl, tolyl, xylyl, furyl, thienyl, pyrrolyl,oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl,furzanyl, pyranyl, pyridyl, pyridazyl, pyrimidryl, pyrazyl,pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidino, piperazinyl,morpholono, indolyl, benzothienyl, quinolyl, isoquinolyl, puryl,quinazolinyl, carbazolyl, acridinyl, phenathridinyl, benzimidazolyl,benzimidazolonyl, benzothiazolyl and phenothiazinyl. Examples ofsubstituents are halogen atom and halo(lower)alkyl, wherein halogen atomand lower alkyl are as defined above.

The term “aryloxy” refers to a group represented by the formula ArO—,wherein Ar is aryl as defined above.

The term “functional derivative” of A includes salts, preferablypharmaceutically acceptable salts, ethers, esters and amides.

Suitable “pharmaceutically acceptable salts” include conventionally usednon-toxic salts, for example a salt with an inorganic base such as analkali metal salt (such as sodium salt and potassium salt), an alkalineearth metal salt (such as calcium salt and magnesium salt), an ammoniumsalt; or a salt with an organic base, for example, an amine salt (suchas methylamine salt, dimethylamine salt, cyclohexylamine salt,benzylamine salt, piperidine salt, ethylenediamine salt, ethanolaminesalt, diethanolamine salt, triethanolamine salt,tris(hydroxymethylamino)ethane salt, monomethyl-monoethanolamine salt,procaine salt and caffeine salt), a basic amino acid salt (such asarginine salt and lysine salt), tetraalkyl ammonium salt and the like.These salts may be prepared by a conventional process, for example fromthe corresponding acid and base or by salt interchange.

Examples of the ethers include alkyl ethers, for example, lower alkylethers such as methyl ether, ethyl ether, propyl ether, isopropyl ether,butyl ether, isobutyl ether, t-butyl ether, pentyl ether and1-cyclopropyl ethyl ether; and medium or higher alkyl ethers such asoctyl ether, diethylhexyl ether, lauryl ether and cetyl ether;unsaturated ethers such as oleyl ether and linolenyl ether; loweralkenyl ethers such as vinyl ether, allyl ether; lower alkynyl etherssuch as ethynyl ether and propynyl ether; hydroxy(lower)alkyl etherssuch as hydroxyethyl ether and hydroxyisopropyl ether; loweralkoxy(lower)alkyl ethers such as methoxymethyl ether and 1-methoxyethylether; optionally substituted aryl ethers such as phenyl ether, tosylether, t-butylphenyl ether, salicyl ether, 3,4-di-methoxyphenyl etherand benzamidophenyl ether; and aryl(lower)alkyl ethers such as benzylether, trityl ether and benzhydryl ether.

Examples of the esters include aliphatic esters, for example, loweralkyl esters such as methyl ester, ethyl ester, propyl ester, isopropylester, butyl ester, isobutyl ester, t-butyl ester, pentyl ester and1-cyclopropylethyl ester; lower alkenyl esters such as vinyl ester andallyl ester; lower alkynyl esters such as ethynyl ester and propynylester; hydroxy(lower)alkyl ester such as hydroxyethyl ester; loweralkoxy(lower) alkyl esters such as methoxymethyl ester and1-methoxyethyl ester; and optionally substituted aryl esters such as,for example, phenyl ester, tolyl ester, t-butylphenyl ester, salicylester, 3,4-di-methoxyphenyl ester and benzamidophenyl ester; andaryl(lower)alkyl ester such as benzyl ester, trityl ester and benzhydrylester.

The amide of A means a group represented by the formula —CONR′R″,wherein each of R′ and R″ is hydrogen, lower alkyl, aryl, alkyl- oraryl-sulfonyl, lower alkenyl and lower alkynyl, and includes forexample, lower alkyl amides such as methylamide, ethylamide,dimethylamide and diethylamide; arylamides such as anilide andtoluidide; and alkyl- or aryl-sulfonylamides such asmethylsulfonylamide, ethylsulfonyl-amide and tolylsulfonylamide.

Examples of Y include, for example, the following groups:

—CH₂—CH₂—CH₂—CH₂—CH₂—CH₂—,

—CH₂—CH═CH—CH₂—CH₂—CH₂—,

—CH₂—CH₂—CH₂—CH₂—CH═CH—,

—CH₂—C≡C—CH₂—CH₂—CH₂—,

—CH₂—CH₂—CH₂—CH₂—O—CH₂—,

—CH₂—CH═CH—CH₂—O—CH₂—,

—CH₂—C≡C—CH₂—O—CH₂—,

—CH₂—CH₂—CH₂—CH₂—CH₂—CH₂—CH₂—

—CH₂—CH═CH—CH₂—CH₂—CH₂—CH₂—

—CH₂—CH₂—CH₂—CH₂—CH₂—CH═CH—,

—CH₂—C═C—CH₂—CH₂—CH₂—CH₂—,

—CH₂—CH₂—CH₂—CH₂—CH₂—CH(CH₃)—CH₂—,

—CH₂—CH₂—CH₂—CH₂—CH(CH₃)—CH₂—,

—CH₂—CH₂—CH₂—CH₂—CH₂—CH₂—CH₂—CH₂—

—CH₂—CH═CH—CH₂—CH₂—CH₂—CH₂—CH₂

—CH₂—CH₂—CH₂—CH₂—CH₂—CH₂—CH═CH—,

—CH₂—C≡C—CH₂—CH₂—CH₂—CH₂—CH₂—, and

—CH₂—CH₂—CH₂—CH₂—CH₂—CH₂—CH(CH₃)—CH₂—.

Further, at least one carbon atom in the aliphatic hydrocarbon of Y isoptionally substituted by oxygen, nitrogen or sulfur.

Preferred A is —COOH or its pharmaceutically acceptable salt or ester.

Preferred X₁ and X₂ are both being halogen atoms, and more preferably,fluorine atoms.

Preferred W₁ is ═O.

Preferred W₂ is

where R₃ and R₉ are both hydrogen atoms.

Preferred Y is an unsubstituted saturated or unsaturated hydrocarbonchain having 6-8 carbon atoms.

Preferred R₁ is a hydrocarbon containing 1-6 carbon atoms, morepreferably, 1-4 carbon atoms. R₁ may have one or two side chains havingone carbon atom.

R₂ is preferably hydrogen.

Most preferred embodiment is a prostaglandin compound of Formula (I) inwhich A is —COOH; Y is (CH₂)₆; W₁ is ═O; W₂ is

wherein R₃ and R₄ are both hydrogen atoms; R₂ is hydrogen atom; X₁ andX₂ are fluorine; and R₁ is (CH₂)₃CH₃ or CH₂CH(CH₃)CH₂CH₃.

The compound of Formula (I) used in the present invention exists as abicyclic compound in a solid state, but in a solvent, a part of thecompound may be in the form of the mono-cyclic tautomer. In the absenceof water, the compound represented by Formula (I) exists predominantlyin the form of the bicyclic structure. In aqueous media, some parts ofthe compound may become in the form of its monocyclic tautomer. It isbelieved that hydrogen bonding occurs between, for example, the ketoneposition at the C-15 position, thereby hindering bicyclic ringformation. In addition, it is believed that the halogen atoms at theC-16 position promote bicyclic ring formation. The tautomerism betweenthe hydroxy at the C-11 position and the keto moiety at the C-15position, shown below, is especially significant in the case ofcompounds having a 13,14 single bond and two fluorine atoms the C-16position.

Accordingly, in the specification and claims, a compound of Formula (I)represented as the bicyclic form also covers its mono-cyclic tautomer.For example, bicyclic and monocyclic forms of a compound having a ketogroup at the C-15 position and halogen atoms at the C-16 position may beas follows.

Further, while the compounds used in the invention may be represented bya name based on the mono-cyclic tautomer regardless of the presence orabsence of the isomers, it is to be noted that such structure or namedoes not intend to exclude the bicyclic type compound.

A preferred compound according to the invention in its monocyclic formcan be named as 13,14-dihydro-15-keto-16,16-difluoro-PGE₁ or13,14-dihydro-15-keto-16,16-difluoro-18(S)-methyl-PGE₁, according toconventional prostaglandin nomenclature.

The compound used in the present invention may be prepared by the methoddisclosed in U.S. Pat. No. 5,284,858 and U.S. Pat. No. 5,739,161 (thesecited references are herein incorporated by reference).

According to the present invention, the subject to be treated may be anymammalian subject including a human. The compound of Formula (I) may beapplied systemically or topically. Usually, the compound may beadministered by oral administration, intranasal administration,inhalational administration, intravenous injection (including infusion),subcutaneous injection, intra rectal administration, transdermaladministration and the like.

The dose may vary depending on the strain of the animal, age, bodyweight, symptom to be treated, desired therapeutic effect,administration route, term of treatment and the like. A satisfactoryeffect can be obtained by systemic or topical administration 1-4 timesper day or continuous administration at the amount of 0.00001-500 μg/kgper day, preferably 0.0001-100 μg/kg, more preferably 0.001-10 μg/kg.

The compound of Formula (I) may preferably be formulated in apharmaceutical composition suitable for administration in a conventionalmanner. The composition may be those suitable for oral administration,intranasal administration, inhalational administration, injection orperfusion as well as it may be an external agent, suppository orpessary.

The composition of the present invention may further containphysiologically acceptable additives. Said additives may include theingredients used with the present compounds such as excipient, diluent,filler, resolvent, lubricant, adjuvant, binder, disintegrator, coatingagent, cupsulating agent, ointment base, suppository base, aerozolingagent, emulsifier, dispersing agent, suspending agent, thickener,tonicity agent, buffering agent, soothing agent, preservative,antioxidant, corrigent, flavor, colorant, a functional material such ascyclodextrin and biodegradable polymer, stabilizer. The additives arewell known to the art and may be selected from those described ingeneral reference books of pharmaceutics.

The amount of the above-defined compound in the composition of theinvention may vary depending on the formulation of the composition, andmay generally be 0.000001-10.0%, more preferably 0.00001-5.0%, mostpreferably 0.0001-1%.

Examples of solid compositions for oral administration include tablets,troches, sublingual tablets, capsules, pills, powders, granules and thelike. The solid composition may be prepared by mixing one or more activeingredients with at least one inactive diluent. The composition mayfurther contain additives other than the inactive diluents, for example,a lubricant, a disintegrator and a stabilizer. Tablets and pills may becoated with an enteric or gastroenteric film, if necessary. They may becovered with two or more layers. They may also be adsorbed to asustained release material, or microcapsulated. Additionally, thecompositions may be capsulated by means of an easily degradable materialsuch gelatin. They may be further dissolved in an appropriate solventsuch as fatty acid or its mono, di or triglyceride to be a soft capsule.Sublingual tablet may be used in need of fast-acting property.

Examples of liquid compositions for oral administration, intranasaladministration or inhalational administration include emulsions,solutions, suspensions, syrups and elixirs and the like. Saidcomposition may further contain a conventionally used inactive diluentse.g. purified water or ethyl alcohol. The composition may containadditives other than the inactive diluents such as adjuvant e.g. wettingagents and suspending agents, sweeteners, flavors, fragrance andpreservatives.

The composition of the present invention may be in the form of sprayingcomposition, which contains one or more active ingredients and may beprepared according to a known method.

Intranasal preparations may be administered as aqueous or oilysolutions, suspensions or emulsions. For the administration of an activeingredient by inhalation, it can be administered in the form of asuspension, solution or emulsion which is present as dry powder or asaerosol, it being possible to use all customary propellants.

Examples of the injectable compositions of the present invention forparenteral administration include sterile aqueous or non-aqueoussolutions, suspensions and emulsions. Diluents for the aqueous solutionor suspension may include, for example, distilled water for injection,physiological saline and Ringer's solution.

Non-aqueous diluents for solution and suspension may include, forexample, propylene glycol, polyethylene glycol, vegetable oils such asolive oil, alcohols such as ethanol and polysorbate. The composition mayfurther comprise additives such as preservatives, wetting agents,emulsifying agents, dispersing agents and the like. They may besterilized by filtration through, e.g. a bacteria-retaining filter,compounding with a sterilizer, or by means of gas or radioisotopeirradiation sterilization. The injectable composition may also beprovided as a sterilized powder composition to be dissolved in asterilized solvent for injection before use.

Another form of the present invention is suppository or pessary, whichmay be prepared by mixing active ingredients into a conventional basesuch as cacao butter that softens at body temperature, and nonionicsurfactants having suitable softening temperatures may be used toimprove absorbability.

As mentioned above, the compound of Formula (I) promotesgastrointestinal bicarbonate secretion, thereby it is useful forprotecting the gastrointestinal tracts from mucosal damage induced byacid, pepsin, certain drugs such as NSAIDs and bacterial infection.

The term “gastrointestinal tract” used in the instant specification andclaims includes upper gastrointestinal tracts such as esophagus,stomach, duodenum and lower gastrointestinal tracts such as smallintestine including jejunum and ileum, and large intestine includingcolon and rectum. Especially the compound of Formula (I) promotes thebicarbonate secretion in the upper gastrointestinal tracts.

The pharmaceutical composition of the present invention may furthercontain other pharmacological ingredients as far as they do notcontradict the purpose of the present invention.

Further details of the present invention will follow with reference totest examples, which, however, are not intended to limit the presentinvention.

EXAMPLE

The effect of Compound A(13,14-dihydro-15-keto-16,16-difluoro-18(S)-methyl-PGE₁) onGastrointestinal bicarbonate secretion was studied.

Seven weeks old male Wistar rats were used in this study. Compound A ata dose of 100 μg/kg was administered orally to the animals three timesdaily for 7 days. Control animals received an equal volume of thevehicle (distilled water containing 0.01% polysorbate 80 and 0.5%ethanol). On the next morning of the final administration (about 17hours after the final administration), a polyethylene catheter (PE10,Becton Dickinson and Company) was inserted into the common bile duct ofthe animal under ether anesthesia. The animals were placed into aBorrmann's cage individually and allowed to recover from the anesthesiafor 1 hour. Bile was collected for 1 hour between 1 and 2 hours afterinserting the catheter. The amount of bicarbonate (HCO₃ ⁻) in the bilewas measured with an automated pH/blood gas analyzer (model 170, CibaCorning Diagnostics Corp.).

In the Compound A group, the amount of bicarbonate secreted into thebile was increased significantly as compared with that of the controlgroup.

TABLE 1 Effect of Compound A on bicarbonate secretion Dose μg/kgBicarbonate secretion (p.o.), TID μmol/hr/100 g body weight Group for 7days n Mean ± S.E. Control — 6 10.16 ± 0.81  Compound A 100 7 13.33 ±1.00* *p < 0.05 compared with control group (Student's t-test)

The result indicates that the compound of Formula (I) promotesbicarbonates secretion in the gastrointestinal tracts, thereby hasprotective action on the gastrointestinal tracts from the mucosaldamage.

While the invention has been described in detail and with reference tospecific embodiments thereof, it will be apparent to one skilled in theart that various changes and modifications can be made therein withoutdeparting from the spirit and scope thereof.

What is claimed is:
 1. A method for promoting bicarbonate secretion inthe upper gastrointestinal tract in a mammalian subject, which comprisesadministering to the subject in need thereof an effective amount of acompound represented by Formula (I) and/or its tautomer:

wherein A is —COOH or its pharmaceutically acceptable salt or ester; X₁and X₂ are both halogen atoms; W₁ is ═O; W₂ is

 wherein R₃ and R₄ are both hydrogen atoms; Y is an unsubstitutedsaturated or unsaturated hydrocarbon chain having 6-8 carbon atoms; R₁is a straight or branched hydrocarbon containing 1-6 carbon atoms; andR₂ is hydrogen; the bond between C-13 and C-14 position is double orsingle bond, and the steric configuration at C-15 position is R, S, or amixture thereof.
 2. The method as described in claim 1, wherein X₁ andX₂ are fluorine atoms.
 3. The method as described in claim 2, wherein Ais —COOH.
 4. The method as described in claim 1, wherein the uppergastrointestinal tract is esophagus, stomach and/or duodenum.
 5. Amethod for protecting the upper gastrointestinal tract from mucosaldamage in a mammalian subject, which comprises administering to thesubject in need thereof an effective amount of a compound represented byFormula (I) and/or its tautomer:

wherein A is —COOH or its pharmaceutically acceptable salt or ester; X₁and X₂ are both halogen atoms; W₁ is ═O; W₂ is

 wherein R₃ and R₄ are both hydrogen atoms; Y is an unsubstitutedsaturated or unsaturated hydrocarbon chain having 6-8 carbon atoms; R₁is a straight or branched hydrocarbon containing 1-6 carbon atoms; andR₂ is hydrogen; the bond between C-13 and C-14 position is double orsingle bond, and the steric configuration at C-15 position is R, S, or amixture thereof.
 6. The method as described in claim 5, wherein themucosal damage is induced by acid.
 7. The method as described in claim5, wherein the mucosal damage is induced by pepsin.
 8. The method asdescribed in claim 5, wherein the mucosal damage is induced bynonsteroidal anti-inflammatory drugs.
 9. The method as described inclaim 5, wherein the mucosal damage is induced by bacterial infection.10. The method as described in claim 5, wherein X₁ and X₂ are fluorineatoms.
 11. The method as described in claim 10, wherein A is —COOH. 12.The method as described in claim 5, wherein the upper gastrointestinaltract is esophagus, stomach and/or duodenum.
 13. The method as describedin claim 1, wherein the compound is13,14-dihydro-15-keto-16,16-difluoro-PGE₁;13,14-dihydro-15-keto-16,16-difluoro-18-methyl-PGE₁; a salt, ether,ester or amide thereof; a tautomer thereof; or a mixture thereof. 14.The method as described in claim 5, wherein the compound is13,14-dihydro-15-keto-16,16-difluoro-PGE₁;13,14-dihydro-15-keto-16,16-difluoro-18-methyl-PGE₁; a salt, ether,ester or amide thereof; a tautomer thereof; or a mixture thereof.